Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Takeda UK Limited, Building 3, Glory Park, Glory Park Avenue, Wooburn Green, BUCKS, HP10 0DF
Patients who have experienced serious adverse events should be monitored for at least 24 hours after removal of Matrifen, or more, as clinical symptoms dictate, because serum fentanyl concentrations decline gradually and are reduced by about 50% 20-27 hours later.
Patients and their carers must be instructed that Matrifen contains an active substance in an amount that can be fatal, especially to a child. Therefore, they must keep all patches out of the sight and reach of children, both before and after use.
Use of Matrifen in the opioid-naïve patient has been associated with very rare cases of significant respiratory depression and/or fatality when used as initial opioid therapy, especially in patients with non-cancer pain. The potential for serious or life-threatening hypoventilation exists even if the lowest dose of Matrifen is used in initiating therapy in opioid-naïve patients, especially in elderly or patients with hepatic or renal impairment. The tendency of tolerance development varies widely among individuals. It is recommended that Matrifen is used in patients who have demonstrated opioid tolerance (see section 4.2).
Some patients may experience significant respiratory depression with Matrifen; patients must be observed for these effects. Respiratory depression may persist beyond the removal of the Matrifen patch. The incidence of respiratory depression increases as the Matrifen dose is increased (see section 4.9). Central nervous system depressants may increase the respiratory depression (see section 4.5).
Concomitant use of Matrifen and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Matrifen concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.
The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).
Matrifen may have more severe adverse effects in patients with chronic obstructive or other pulmonary disease. In such patients, opioids may decrease respiratory drive and increase airway resistance.
Tolerance, physical dependence, and psychological dependence may develop upon repeated administration of opioids.
Fentanyl can be abused in a manner similar to other opioid agonists. Abuse or intentional misuse of Matrifen may result in overdose and/or death. Patients with a prior history of drug dependence/alcohol abuse are more at risk to develop dependence and abuse in opioid treatment. Patients at increased risk of opioid abuse may still be appropriately treated with modified-release opioid formulations; however, these patients will require monitoring for signs of misuse, abuse, or addiction.
Matrifen should be used with caution in patients who may be particularly susceptible to the intracranial effects of CO2 retention such as those with evidence of increased intracranial pressure, impaired consciousness, or coma. Matrifen should be used with caution in patients with brain tumors.
Fentanyl may produce bradycardia and should therefore be administered with caution to patients with bradyarrhythmias.
Opioids may cause hypotension, especially in patients with acute hypovolaemia. Underlying, symptomatic hypotension and/or hypovolaemia should be corrected before treatment with fentanyl transdermal patches is initiated.
Because fentanyl is metabolised to inactive metabolites in the liver, hepatic impairment might delay its elimination. If patients with hepatic impairment receive Matrifen, they should be observed carefully for signs of fentanyl toxicity and the dose of Matrifen reduced if necessary (see section 5.2).
Even though impairment of renal function is not expected to affect fentanyl elimination to a clinically relevant extent, caution is advised because fentanyl pharmacokinetics has not been evaluated in this patient population (see section 5.2). If patients with renal impairment receive Matrifen they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary. Additional restrictions apply to opioid-naïve patients with renal impairment (see section 4.2).
Fentanyl concentrations may increase if the skin temperature increases (see section 5.2).
Therefore, patients with fever should be monitored for opioid undesirable effects and the Matrifen dose should be adjusted if necessary. There is a potential for temperature-dependent increases in fentanyl released from the system resulting in possible overdose and death.
All patients should be advised to avoid exposing the Matrifen application site to direct external heat sources such as heating pads, electric blankets, heated water beds, heat or tanning lamps, sunbathing, hot water bottles, prolonged hot baths, saunas and hot whirlpool spa baths
Caution is advised when Matrifen is co-administered with medicinal products that affect the serotonergic neurotransmitter systems.
The development of a potentially life-threatening serotonin syndrome may occur with the concomitant use of serotonergic active substances such as Selective Serotonin Re-uptake Inhibitors (SSRIs) and Serotonin Norepinephrine Re-uptake Inhibitors (SNRIs), and with active substances which impair metabolism of serotonin (including Monoamine Oxidase Inhibitors [MAOIs]). This may occur within the recommended dose.
Serotonin syndrome may include mental-status changes (e.g. agitation, hallucinations, coma), autonomic instability (e.g. tachycardia, labile blood pressure, hyperthermia), neuromuscular abnormalities (e.g. hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea).
If serotonin syndrome is suspected, treatment with Matrifen should be discontinued.
The concomitant use of Matrifen with cytochrome P450 3A4 (CYP3A4) inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong both the therapeutic and adverse effects, and may cause serious respiratory depression. Therefore, the concomitant use of Matrifen and CYP3A4 inhibitors is not recommended unless the benefits outweigh the increased risk of adverse effects. Generally, a patient should wait for 2 days after stopping treatment with a CYP3A4 inhibitor before applying the first Matrifen patch. However, the duration of inhibition varies and for some CYP3A4 inhibitors with a long elimination half-life, such as amiodarone, or for time-dependent inhibitors such as erythromycin, idelalisib, nicardipine and ritonavir, this period may need to be longer. Therefore, the product information of the CYP3A4 inhibitor must be consulted for the active substance’s half-life and duration of the inhibitory effect before applying the first Matrifen patch. A patient who is treated with Matrifen should wait at least 1 week after removal of the last patch before initiating treatment with a CYP3A4 inhibitor. If concomitant use of Matrifen with a CYP3A4 inhibitor cannot be avoided, close monitoring for signs or symptoms of increased or prolonged therapeutic effects and adverse effects of fentanyl (in particular respiratory depression) is warranted, and the Matrifen dosage must be reduced or interrupted as deemed necessary (see section 4.5).
Accidental transfer of a fentanyl patch to the skin of a non-patch wearer (particularly a child), while sharing a bed or being in close physical contact with a patch wearer, may result in an opioid overdose for the non-patch wearer. Patients should be advised that if accidental patch transfer occurs, the transferred patch must be removed immediately from the skin of the non-patch wearer (see section 4.9).
Data from intravenous studies with fentanyl suggest that elderly patients may have reduced clearance, a prolonged half-life and they may be more sensitive to the active substance than younger patients. If elderly patients receive Matrifen, they should be observed carefully for signs of fentanyl toxicity and the dose reduced if necessary (see section 5.2).
Opioids increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. The resultant prolongation in gastrointestinal transit time may be responsible for the constipating effect of fentanyl. Patients should be advised on measures to prevent constipation and prophylactic laxative use should be considered. Extra caution should be used in patients with chronic constipation. If paralytic ileus is present or suspected, treatment with Matrifen should be stopped.
Non-epileptic (myo)clonic reactions can occur. Caution should be exercised when treating patients with myasthenia gravis.
The concomitant use of buprenorphine, nalbuphine or pentazocine is not recommended (see also section 4.5).
Matrifen should not be administered to opioid naïve paediatric patients (see section 4.2). The potential for serious or life-threatening hypoventilation exists regardless of the dose of Matrifen transdermal system administered.
Matrifen has not been studied in children under 2 years of age. Matrifen should be administered only to opioid-tolerant children age 2 years or older (see section 4.2).
To guard against accidental ingestion by children, use caution when choosing the application site for Matrifen (see section 4.2 and 6.6) and monitor adhesion of the patch closely.
The concomitant use of other central nervous system depressants, (including opioids, sedatives such as benzodiazepines or related drugs, hypnotics, general anaesthetics, phenothiazines, tranquilizers, sedating antihistamines, and alcoholic beverages) and skeletal muscle relaxants, may produce additive CNS depressant effects; hypotension, profound sedation, hypoventilation, respiratory depression, coma or death may occur. Therefore, the use of any of these medicinal products concomitantly with Matrifen requires special patient care and observation.
The dose and duration of concomitant use should be limited (see section 4.4).
Matrifen is not recommended for use in patients who require the concomitant administration of an MAOI. Severe and unpredictable interactions with MAOIs, involving the potentiation of opiate effects or the potentiation of serotoninergic effects, have been reported. Therefore, Matrifen should not be used within 14 days after discontinuation of treatment with MAOIs.
Co-administration of fentanyl with a serotonergic medicinal products, such as a Selective Serotonin Re-uptake Inhibitor (SSRI) or a Serotonin Norepinephrine Re-uptake Inhibitor (SNRI) or a Monoamine Oxidase Inhibitor (MAOI), may increase the risk of serotonin syndrome, a potentially life threatening condition.
The concomitant use of buprenorphine, nalbuphine or pentazocine is not recommended. They have high affinity to opioid receptors with relatively low intrinsic activity and therefore partially antagonise the analgesic effect of fentanyl and may induce withdrawal symptoms in opioid dependent patients (see also Section 4.4).
Fentanyl, a high clearance active substance, is rapidly and extensively metabolised mainly by CYP3A4.
The concomitant use of Matrifen with cytochrome P450 3A4 (CYP3A4) inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong both the therapeutic and adverse effects, and may cause serious respiratory depression. The extent of interaction with strong CYP3A4 inhibitors is expected to be greater than with weak or moderate CYP3A4 inhibitors.
Cases of serious respiratory depression after coadministration of CYP3A4 inhibitors with transdermal fentanyl have been reported, including a fatal case after coadministration with a moderate CYP3A4 inhibitor. The concomitant use of CYP3A4 inhibitors and Matrifen is not recommended, unless the patient is closely monitored (see section 4.4). Examples of active substances that may increase fentanyl concentrations include: amiodarone, cimetidine, clarithromycin, diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, nefazodone, ritonavir, verapamil and voriconazole (this list is not exhaustive). After coadministration of weak, moderate or strong CYP3A4 inhibitors with short-term intravenous fentanyl administration, decreases in fentanyl clearance were generally <25%, however with ritonavir (a strong CYP3A4 inhibitor), fentanyl clearance decreased on average 67%. The extent of the interactions of CYP3A4 inhibitors with long-term transdermal fentanyl administration is not known, but may be greater than with short-term intravenous administration.
The concomitant use of transdermal fentanyl with CYP3A4 inducers may result in a decrease in fentanyl plasma concentrations and a decreased therapeutic effect. Caution is advised upon concomitant use of CYP3A4 inducers and Matrifen. The dose of Matrifen may need to be increased or a switch to another analgesic active substance may be needed. A fentanyl dose decrease and careful monitoring is warranted in anticipation of stopping concomitant treatment with a CYP3A4 inducer. The effects of the inducer decline gradually and may result in increased fentanyl plasma concentrations, which could increase or prolong both the therapeutic and adverse effects, and may cause serious respiratory depression. Careful monitoring should be continued until stable drug effects are achieved. Examples of active substance that may decrease fentanyl plasma concentrations include: carbamazepine, phenobarbital, phenytoin and rifampicin (this list is not exhaustive).
Interaction studies have only been performed in adults.
There are no adequate data from the use of Matrifen in pregnant women. Studies in animals have shown some reproductive toxicity (see section 5.3). The potential risk for humans is unknown, although fentanyl as an IV anesthetic has been found to cross the placenta in early human pregnancies. Neonatal withdrawal syndrome has been reported in newborn infants with chronic maternal use of Matrifen during pregnancy. Matrifen should not be used during pregnancy unless clearly necessary.
Use of Matrifen during childbirth is not recommended because it should not be used in the management of acute or postoperative pain (see section 4.3). Moreover, because fentanyl passes through the placenta, the use of Matrifen during childbirth might result in respiratory depression in the newborn infant.
Fentanyl is excreted into breast milk and may cause sedation/respiratory depression in a breastfed infant. Breastfeeding should therefore be discontinued during treatment with Matrifen and for at least 72 hours after removal of the patch.
There are no clinical data on the effects of fentanyl on fertility. Some studies in rats have revealed reduced fertility and enhanced embryo mortality at maternally toxic doses (see section 5.3).
Matrifen may impair mental and/or physical ability required for the performance of potentially hazardous tasks such as driving or operating machinery.
This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:
The safety of transdermal fentanyl was evaluated in 1565 adult and 289 paediatric subjects who participated in 11 clinical trials (1 double-blind, placebo-controlled; 7 open-label, active-controlled; 3 open-label, uncontrolled) used for the management of chronic malignant or non-malignant pain. These subjects received at least one dose of transdermal fentanyl and provided safety data. Based on pooled safety data from these clinical trials, the most commonly reported (i.e. ≥10% incidence) adverse drug reactions (ADRs) were: nausea (35.7%), vomiting (23.2%), constipation (23.1%), somnolence (15.0%), dizziness (13.1%), and headache (11.8%).
The adverse reactions reported with the use of transdermal fentanyl from these clinical studies, including the above-mentioned adverse reactions, and from post-marketing experiences are listed below in Table 5.
The displayed frequency categories use the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from the available clinical trial data). The adverse reactions are presented by System Organ Class and in order of decreasing seriousness within each frequency category.
Table 5. Adverse Drug Reactions in Adult and Paediatric Subjects:
Common: Hypersensitivity
Not Known: Anaphylactic shock, Anaphylactic reaction, Anaphylactoid reaction
Common: Anorexia
Common: Insomnia, Depression, Anxiety, Confusional state, Hallucination
Uncommon: Agitation, Disorientation, Euphoric mood
Very Common: Somnolence, Dizziness, Headache
Common: Tremor, Paraesthesia
Uncommon: Hypoaesthesia, Convulsion (including clonic convulsions and grand mal convulsion), Amnesia, Depressed level of consciousness, Loss of consciousness
Uncommon: Vision blurred
Rare: Miosis
Common: Vertigo
Cardiac Disorders
Common: Palpitations, Tachycardia
Uncommon: Bradycardia, Cyanosis
Common: Hypertension
Uncommon: Hypotension
Common: Dyspnoea
Uncommon: Respiratory depression, Respiratory distress
Rare: Apnoea, Hypoventilation
Not Known: Bradypnoea
Very Common: Nausea, Vomiting, Constipation
Common: Diarrhoea, Dry mouth, Abdominal pain, Abdominal pain upper, Dyspepsia
Uncommon: Ileus
Rare: Subileus
Common: Hyperhidrosis, Pruritus, Rash, Erythema
Uncommon: Eczema, Dermatitis allergic, Skin disorder, Dermatitis, Dermatitis contact
Common: Muscle spasms
Uncommon: Muscle twitching
Common: Urinary retention
Uncommon: Erectile dysfunction, Sexual dysfunction
General Disorders and Administration Site Conditions
Common: Fatigue, Oedema peripheral, Asthenia, Malaise, Feeling cold
Uncommon: Application site reaction, Influenza like illness, Feeling of body temperature change, Application site hypersensitivity, Drug withdrawal syndrome, Pyrexia*
Rare: Application site dermatitis, Application site eczema
* the assigned frequency (uncommon) is based on analyses of incidence including only adult and paediatric clinical study subjects with non-cancer pain.
The safety of fentanyl transdermal patch was evaluated in 289 paediatric subjects (<18 years) who participated in 3 clinical studies for the management of chronic or continuous pain of malignant or non-malignant origin. These subjects received at least one dose of fentanyl transdermal patch and provided safety data (see section 5.1).
The safety profile in children and adolescents treated with fentanyl transdermal patch was similar to that observed in adults. No risk was identified in the paediatric population beyond that expected with the use of opioids for the relief of pain associated with serious illness and there does not appear to be any paediatric-specific risk associated with fentanyl transdermal patch use in children as young as 2 years old when used as directed.
Based on pooled safety data from these 3 clinical trials in paediatric subjects, the most commonly reported (i.e. ≥10% incidence) adverse reactions were vomiting (33.9%), nausea (23.5%), headache (16.3%), constipation (13.5%), diarrhoea (12.8%), and pruritus (12.8%).
Tolerance, physical dependence, and psychological dependence can develop on repeated use of fentanyl (see section 4.4).
Opioid withdrawal symptoms (such as nausea, vomiting, diarrhoea, anxiety, and shivering) are possible in some patients after conversion from their previous opioid analgesic to fentanyl transdermal patch or if therapy is stopped suddenly (see section 4.2).
There have been very rare reports of newborn infants experiencing neonatal withdrawal syndrome when mothers chronically used transdermal fentanyl during pregnancy (see section 4.6).
Cases of serotonin syndrome have been reported when fentanyl was administered concomitantly with highly serotonergic drugs (see sections 4.4. and 4.5).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.yellowcard.mhra.gov.uk.
To prevent interference with the adhesive properties of Matrifen, no creams, oils, lotions or powder should be applied to the skin area when the Matrifen patch is applied.
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